Herbal remedies involving the Sweet wormwood (Artemisia annua) have been traditionally used in China as a treatment for a variety of ailments, including fever and rheumatism. The major active ingredient artemisinin was identified and isolated in the 1970s, and its particular activity as a compound targeting malaria was investigated ever since.
2.1 Artemisinins
Studies involving a structure-activity relationship analyses of the original parental artemisinin molecule have focused on developing the hemisuccinate ester of artemisinin known as artesunate (ART), which taken together with its siblings have resulted in a family of compounds collectively known as the “artemisinins.” These agents are amongst the most potent and rapidly-acting anti-malarial agents known, and are efficacious against parasites that are resistant to established anti-malarial drugs such as chloroquine and pyrimethamine (Li et al., 1984, Lancet. 2:1360-1361; Krishna et al., 2008. Trends Phurniacol Sci. 29:520-7). The mechanism of action of artemisinins has yet to be defined, but studies have described a role for free-radicals. Specifically, induced de novo production of reactive hydroxyl moieties and superoxides within the malarial parasite, have been reported that damages intracellular processes and causes death (Meshnick S R. 2002. Int J Parasitol. 32:1655-60; Golenser et al., 2006 Int Parasitol. 36:1427-41). In spite of the lack of a definitive mechanism, the World Health Organisation have recommended that all anti-malarial therapies should contain an artemisinin component, especially when used as a first line treatment.
There is growing evidence supporting a role of ART and other artemisinins in cancer therapy (Efferth et al., 2001, Int Oncol, 18:767-73; Efferth et at, 2007, PLoS One, 2:e693; Efferth et al., 2007, Trends Mol Med, 13:353-61; Li et at, 2007, Int J Cancer; 121:1360-5; Chen et al., 2009, Anticancer Drugs, 20:131-40; Du et at, 2010, Cancer Chemother Pharmacol, 65:895-902; Gravett et al., 2010, Cancer Chemother Pharmacol, [Epub ahead of print]; Michaelis et al., 2010, Biochem Pharmacol, 79:130-6). Anti-proliferative activity has been described in vitro for this class of agent in a wide spectrum of tumour cell lines as well as in primary material derived from patients. The mechanism(s) underlying these activities are unclear, and have included i) actions on cell cycle proteins that determine transit through G1 restriction (Hou et al., 2008, Clin Cancer Res, 14:5519-30); ii) disruptions to the intrinsic apoptotic pathway that it drive towards a pro-apoptotic outcome (Du et al., 2010, Cancer Chemother Pharmacol, 65:895-902; Michaelis et at, 2010, Biochem Pharmacol, 79:130-6; Zhou et al., 2008, Anticancer Drugs, 19:247-55); iii) anti-angiogenic and anti-metastatic properties (Anfosso et al., 2006, Pharmacogenomics J, 6:269-78; Zhou et at, 2007, Vascul Pharmacol, 47:131-8; Rasheed et al., 2010, Int J Cancer, 127(6):1475-85); and iv) inhibition of NF-kB (Li et al., 2009 Int J Hematol, 90:513-21; Li et al., 2010, Int Immunopharmacol, 10:344-50). The diversity in the targets of ART, naturally lends support to the possibility that it be used in combination with other agents that mutually support each other (Liu W M, 2008, Curr Clin Pharmacol, 3:108-17). Indeed, there were reports on non-antagonistic interactions between ART and ART-related compound with common anti-cancer drugs (Gravett et al., 2010, Cancer Chemother Pharmacol, [Epub ahead of print]; Li et al., 2010, Int Immunopharmacol, 10:344-50) as well as enhanced activities in combinations with more novel treatment modalities such as erlotinib and rituximab (Efferth et at, 2004, Biochem Pharmacol. 67:1689-1700: Sieber et al., 2009, Int J Oncol, 35:149-58).
There is currently only limited and simplistic published data exploring the value of ART as a combination partner in treatment regimens. These studies have used simple approaches to studying drug-drug interactions, and as a consequence, their conclusions are still open to debate.
2.2 Artemisinin Derivatives (ARTds)
Structure-activity relationship analyses of the original parental artemisinin molecule have also yielded a novel class of trioxanes, designated the artemisinin derivatives (ARTds), which are amongst the most potent antimalarial agents known. ARTds are thought to target multiple cellular processes within the Plasmodium sp. parasite that causes malaria, and for that reason can be more than a 1.000 times more effective than the more standard antimalarial treatments such as chloroquine and pyrimethamine (Haynes et al., 2006, Angew. Chem. Int. Ed Engl. 45, 2082-2088). Furthermore, the ARTds are much faster acting than most of these treatments (Li et al., 1984, Lancet, 2: 1360-1361; Li, et al., 1994, Trans. R. Soc. Trop. Med. Hyg. 88 Suppl 1, S5-S6), and can also clear drug-resistant strains of the parasite. These impressive qualities and activities have resulted in the World Health Organisation recommending that all antimalarials be combined with an ARTd component when used first line (WHO Guidelines for the treatment of malaria (2006)).
One notable example of a ARTd is artemisone (ATM). ATM has emerged as a therapeutic candidate and possesses sustained activity in plasma compared to sister compounds. This renders it significantly more active against the most common malarial parasite Plasmodium falciparum than other antimalarial drugs (Haynes et al., 2006, Angew. Chem. Int. Ed Engl. 45, 2082-2088; Vivas et al., 2007, J. Antimicrob. Chemother. 59, 658-665; Ramharter et al., 2006. Am. J. Trop. Med. Hyg. 75: 637-639). It has almost negligible toxicity (Nagelschmitz et al., 2008. Antimicrob. Agents Chemother. 52: 3085-3091), and benefits from having low production costs by being synthesised from the parental artemisinin compound in just 3-steps.
In recent years the ARTds have also been shown to have anticancer properties, through their ability to reduce cell number in a variety of solid tumours in vitro (Woerdenbag et al., 1993, J. Nat. Prod. 56: 849-856; Efferth et al., 2001, Int. J. Oncol. 18: 767-773; Chen et al. 2003, Pharmacol. Res. 48: 231-236; Nakase et al., 2008. Int. J. Pharm. 354: 28-33) and in ex vivo animal models (Li et al. 2007, Int. J. Cancer 121: 1360-1365). Activity has also been seen in humans (Berger et al. 2005, Oncol. Rep. 14, 1599-1603; Singh et al. 2006. Integr. Cancer Ther. 5: 391-394), and a recent phase II study in patients with lung cancer reported ARTd combinations could extend short-term survival and time-to-progression rates (Zhang et al., 2008, Zhong. Xi. Yi. Jie. Xue. Bao. 6: 134-138). Studies have identified several potential mechanisms for the ARTds against cancer cells. However, a single mechanism has yet to be defined. The ARTds have been shown to be anti-proliferative through that action on key cell cycle regulatory proteins such as p21waf1cip1 and cyclin D1 (Hou et al., 2008, Clin. Cancer Res. 14: 5519-5530); pro-apoptotic by manipulating the Bax:Bcl-2 rheostat (Singh, et al. 2004, Anticancer Res. 24: 2277-2280; Zhou et al., 2008, Anticancer Drugs 19: 247-255); anti-angiogenic by targeting vascular endothelial growth factor (Chen et al., 2004, Cancer Chemother. Pharmacol. 53:423-432; Wartenberg et al., 2003, Lab Invest. 83: 1647-1655); and anti-migratory through their effects on αVβ3 integrins (Buommino et al., 2009, Invest New Drugs 27: 412-418). The multi-modal character of these classically antimalarial drugs, allied to their low host toxicity even at high doses (Ribeiro et al., 1998, Med. Trop. (Mars.) 58: 50-53; Gordi et al., 2004, Toxicol. Lett. 147: 99-107), reinforce their development as a novel anti-cancer agent.
It has been known for some time that the efficacy of ARTds is significantly enhanced when used in combination with other agents, which is an approach that may be beneficial in cancer. Indeed, ARTds have already shown some synergy with common chemotherapy (Adjuik et al., 2004, Lancet, 363 (9402):9-17). Furthermore, cancer cells can become addicted to certain pathways, which ultimately lead to drug resistance when single agents that target specific pathways are used (Liu W M. 2008, Curr Clin Pharmacol., 2:108-17). Consequently, using drugs that display a wider target-window, such as the ARTds, in combination with more established cytotoxic drugs may improve overall activity.
Citation of any references in this Section of the application is not to be construed as an admission that such references is prior art to the present application.